Closing the Myeloma Treatment Gap Between Clinical Trials and Clinical Practice
For patients with relapsed or refractory multiple myeloma, the journey between hope and reality can be fraught with uncertainty. While clinical trials demonstrate what's possible under ideal conditions, doctors and patients desperately need to know what works in the messy reality of everyday clinical practice—with older patients, those with additional health problems, and people who would typically be excluded from rigorous research studies.
Recent research has quantified this difference, showing that real-world patients face a 51% higher risk of disease progression or death compared to their clinical trial counterparts 1 . This makes the recent UK-wide findings on the isatuximab combination therapy particularly noteworthy—and encouraging for the myeloma community.
Higher risk of progression/death in real-world vs trial patients
Cancer centers across the UK participated
Patients included in the real-world study
Multiple myeloma is a cancer of plasma cells that originates in the bone marrow, causing devastating bone damage, anemia, and kidney problems. While still considered incurable, the treatment landscape has transformed dramatically over the past two decades with the introduction of novel drug classes including immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies 2 .
Most patients experience multiple relapses, each requiring new strategies. When resistance develops to both IMiDs and PIs, options narrow considerably.
Between January 2020 and May 2021, 24 cancer centers across the United Kingdom participated in a retrospective study evaluating the real-world performance of isatuximab in combination with pomalidomide and dexamethasone (IsaPomDex) 2 . This collaboration provided a broad, representative picture of how this regimen performs outside the constraints of clinical trials.
The study included 107 patients with relapsed/refractory multiple myeloma who had received at least one prior line of therapy. These were not the carefully selected patients typically enrolled in clinical trials—they represented the challenging reality of myeloma practice:
Median Age (years)
With Renal Impairment
Median Prior Lines of Therapy
Patients received the standard IsaPomDex regimen: isatuximab intravenous infusion at 10 mg/kg (weekly during cycle 1, then fortnightly), plus oral pomalidomide 4 mg on days 1-21, and weekly dexamethasone at age-adjusted doses 2 . The median number of treatment cycles administered was 7, reflecting the real-world challenges of maintaining therapy in this fragile population.
The primary endpoint of the UK study was overall response rate (ORR), with secondary endpoints including progression-free survival (PFS), duration of response (DOR), and overall survival (OS) 2 . The results demonstrated that the isatuximab combination maintained impressive efficacy despite the less-selected patient population:
| Outcome Measure | UK Real-World Study | ICARIA-MM Trial |
|---|---|---|
| Overall Response Rate | 66.4% | 60% |
| ≥Very Good Partial Response | 31.8% | 33.8% (increased to 38.3% in updated analysis) |
| Partial Response | 34.6% | 26.2% |
| Median Progression-Free Survival | 10.9 months | 11.5 months (primary analysis) |
| Median Duration of Response | 10.3 months | 10.3 months (monotherapy pooled analysis) |
| Median Overall Survival | 18.8 months | 24.6 months (updated analysis) |
The consistency of these results across different settings is remarkable. The UK real-world ORR of 66.4% closely matched the ICARIA-MM trial results, while the median PFS of 10.9 months aligned well with the 11.5 months reported in the pivotal trial 2 4 . Even more impressive was the identical median duration of response of 10.3 months seen in both the UK study and a pooled analysis of isatuximab monotherapy trials 2 5 .
The UK researchers dug deeper to understand how different patient subgroups responded to treatment. Unlike clinical trials that often exclude older patients and those with additional health conditions, this real-world analysis specifically evaluated these groups:
No significant PFS difference was observed by age:
Comorbidity burden did not significantly affect outcomes:
Renal impairment was associated with inferior PFS:
These findings are particularly important for clinical decision-making, suggesting that age and comorbidity burden alone should not preclude patients from receiving this effective combination, while highlighting the need for special attention to patients with kidney impairment.
Additional real-world evidence from Italy further strengthens these findings. In a study of 270 patients, researchers reported an even higher ORR of 74.1% and median PFS of 15.7 months 6 . This larger dataset also included more challenging patient profiles, with 29.3% having high-risk cytogenetics and 20% being refractory to daratumumab (another anti-CD38 antibody)—groups typically excluded from initial clinical trials 6 .
The UK safety analysis revealed that 87.9% of patients experienced adverse events of any grade after a median of 4 cycles 2 . While this number appears high, most events were manageable with standard supportive care.
| Adverse Event | UK Real-World Study (%) | ICARIA-MM Trial (%) |
|---|---|---|
| Neutropenia | 45.8% | 62.5% (Grade 4) |
| Infections | 18.7% | 23.0% (Pneumonia, Grade ≥3) |
| Thrombocytopenia | 14.0% | 13.0% (Grade ≥3, combined with anemia) |
| Anemia | Not specified | 11.9% (Grade ≥3) |
The most common grade 3 or higher adverse events in the UK real-world population were neutropenia (45.8%), infections (18.7%), and thrombocytopenia (14.0%) 2 . Interestingly, the rate of severe neutropenia was notably lower than that reported in the ICARIA-MM trial (45.8% vs 62.5% grade 4), possibly reflecting different management strategies in routine practice or underreporting of asymptomatic laboratory abnormalities 2 6 .
The Italian real-world study similarly reported lower rates of grade 3/4 neutropenia (56.3% vs 62.5%) and thrombocytopenia (15.9% vs approximately 20% in trials), suggesting that real-world management strategies may effectively mitigate some toxicities 6 .
Supportive care plays a crucial role in managing these side effects:
| Research Tool | Function and Significance |
|---|---|
| Isatuximab | Anti-CD38 monoclonal antibody that triggers multiple mechanisms of action against myeloma cells |
| Pomalidomide | Third-generation immunomodulatory drug that enhances immune response against myeloma |
| Dexamethasone | Corticosteroid that reduces inflammation and has direct anti-myeloma effects |
| Flow Cytometry | Technology for detecting CD38 expression on myeloma cells |
| Fluorescence In Situ Hybridization (FISH) | Method for identifying high-risk cytogenetic abnormalities |
| International Myeloma Working Group Criteria | Standardized response criteria enabling consistent outcome assessment across studies |
| Common Terminology Criteria for Adverse Events | Standardized system for grading and reporting treatment side effects |
The compelling evidence from the UK-wide real-world study and supporting international data sends an important message to clinicians and patients: the isatuximab combination maintains its efficacy outside the idealized world of clinical trials. This convergence of trial and real-world outcomes is particularly significant given that real-world myeloma patients typically experience outcomes that are substantially worse than those reported in clinical trials 1 .
The implications extend beyond confirming efficacy—they highlight the importance of considering older patients and those with comorbidities for active treatment rather than defaulting to palliative approaches based on age alone.
For the myeloma community, these findings represent more than just validation of a single treatment regimen—they demonstrate the power of real-world evidence to bridge the gap between clinical research and everyday practice.
As the Italian researchers concluded, "IsaPd is effective and safe in a real-world setting for relapsed or refractory MM patients who received 2 prior lines of therapy" 6 .
As research continues, the focus will shift to optimizing sequencing strategies, identifying reliable biomarkers for response, and developing effective combinations for the most challenging cases, such as patients refractory to other CD38-targeted therapies 8 . What remains clear is that real-world evidence will continue to play a crucial role in translating trial results into meaningful improvements in patient care.